Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, and up to one-third of the worlds population is estimated to be infected with this pathogen.1 The majority of infected individuals remain in an inactive state, referred to as latent TB infection (LTBI), which is characterized by a lack of symptoms or an ability to infect others. However, LTBI can be reactivated and develop into active disease. TB is particularly problematic in individuals infected with human immunodeficiency virus (HIV), as individuals are 26 times more likely to develop active TB infection than HIV-negative individuals,1 with increasing risk as CD4 T lymphocyte counts decline and viral loads increase. TB is one of the most common opportunistic infections in the HIV population worldwide, and in 2014, HIV-positive individuals accounted for 12% of newly developed TB cases. Furthermore, around 25% of all TB deaths were accounted for by those infected with HIV, and 33% of HIV/acquired immunodeficiency syndrome (AIDS) deaths were attributed to TB. The majority of TB cases and deaths are reported in developing countries in Africa and Asia. Higher-income countries, such as the United States, are associated with much lower incidence rates. Nevertheless, TB still poses a significant public health problem. In order to reduce the morbidity and mortality observed in individuals with HIV, appropriate diagnosis and treatment of active and LTBI is essential. Currently, the first-line treatment recommendations for LTBI in HIV-positive individuals include (1) isoniazid (INH) 300 mg daily + pyridoxine 25 mg daily for 9 months or (2) INH 900 mg twice weekly (as part of directly observed therapy DOT) + pyridoxine 25 mg daily for 9 months. Alternative treatment options include (1) rifampin (RIF) 600 mg given orally once daily for 4 months, or (2) rifabutin (RFB) (dose-adjusted for concomitant antiretroviral ARV drugs) for 4 months. INH-based therapies are highly effective for LTBI treatment. However, adherence and treatment completion is low in both HIV-infected and uninfected individuals due to long treatment courses and high pill burden. Once weekly rifapentine (RPT) and INH is another more recently added option to available LTBI treatments in HIV. This regimen was found to be similar in efficacy to INH 300 mg daily for 6 months and 9 months9 in HIV-infected individuals with LTBI not on antiretroviral therapy (ART), and noninferior to daily INH given for 9 months in a largely HIV-negative population. RPT + INH is an attractive therapeutic option for LTBI as it is dosed once weekly over 12 weeks, can be given as part of DOT treatment support, and is well tolerated by patients receiving this therapy. Collectively, these advantages translate into higher rates of adherence comparatively to INH therapy, which requires daily dosing and 6 to 9 months of therapy (82%-95% vs. 48%-85%, respectively). Despite these potential benefits, the use of once weekly RPT with INH is limited in HIV-infected adults on ART in the US due to the lack of data on drug interactions between these agents. Once-weekly RPT + INH is only recommended in patients receiving efavirenz (EFV)- or raltegravir (RAL)-based regimens (in combination with either abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine). As rifamycins can cause significant cytochrome P450 isozyme (CYP) 3A and P glycoprotein (P-gp) transporter induction with daily administration, prospective drug interaction studies between RIF or RFB and ARV agents have informed clinicians of whether to avoid certain combinations or make appropriate dose adjustments. However, the extent of interaction that may be observed with once weekly RPT is unknown and should be further investigated. Furthermore, although INH is not suspected to interact significantly with ARVs, its role in modulating transporter-mediated drug interactions is unknown and should also be further investigated. Tenofovir alafenamide (TAF) is a preferred backbone agent by the current Department of Health and Human Services ARV guidelines and is a part of multiple recommended first-line regimens for the treatment of HIV. However, the use of TAF with rifamycins, including RPT, is not recommended due to potential drug interactions. Thus, the purpose of this study is to determine the effects of concomitant RPT and INH administration on the steady state pharmacokinetics (PK) of plasma TAF, plasma tenofovir (TFV), and intracellular TFV diphosphate (dp). This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate the steady state PK of TAF, TFV, TFV-dp with coadministration of once weekly RPT +INH given at doses used to treat LTBI. The study will consist of two phases: (1) TAF once daily alone (days 1-14) and (2) TAF once daily + weight based RPT + INH once weekly (days 15-32). Participants will undergo periodic serial ARV PK blood draws on days 14, 22, and 31. TAF, TFV, and TFV-dp PK will be determined using non-compartmental methods. The following PK parameters will be compared between phases: area under the curve over the dosing interval in plasma and PBMCs (intracellular), maximum plasma and intracellular concentrations, time to maximum plasma and intracellular concentrations, terminal half-life, apparent oral clearance, and minimum plasma and intracellular concentrations. Adverse events will be graded and recorded.